Lapatinib is indicated for use in combination with:

Capecitabine For the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2), and who have previously received therapy including an anthracycline, a taxane, and trastuzumab. Limitation of Use: Patients should have demonstrated disease progression on trastuzumab before starting treatment with lapatinib in combination with capecitabine.

Letrozole: For the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses HER2, where hormonal therapy is appropriate. The combination of lapatinib with an aromatase inhibitor has not been directly compared with trastuzumab-containing chemotherapy regimens for metastatic breast cancer.

Lapatinib is a 4-anilinoquinazoline kinase inhibitor that targets the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and Human Epidermal Receptor Type 2 (HER2 [ErbB2]). Lapatinib shows an inhibitory effect with an IC50 value of about 13 nM, which is sustained and reversible. An additive effect has been observed in in vitro studies when Lapatinib is used with 5-FU (the active metabolite of Capecitabine) across multiple tumor cell lines. Its growth inhibitory effects were also demonstrated in Trastuzumab-conditioned cell lines, suggesting no cross-resistance between the two drugs. Hormone receptor-positive breast cancer cells expressing ER and/or PgR that co-express HER2 tend to be resistant to endocrine therapy. Similarly, hormone receptor-positive breast cancer cells initially lacking EGFR or HER2 may upregulate these receptors during resistance to endocrine therapy.

Absorption: Lapatinib is incompletely but variably absorbed after oral administration. Serum levels appear within about 0.25 hours (range 0–1.5 hours), and peak concentrations (Cmax) are reached around 4 hours after dosing. Steady state is achieved within 6–7 days with daily dosing, reflecting an effective half-life of about 24 hours. At a dose of 1,250 mg/day, mean Cmax is approximately 2.43 mcg/mL and AUC is about 36.2 mcg·h/mL. Divided dosing increases exposure compared to once-daily dosing. Food increases systemic exposure significantly—about 2.5–3 fold with low-fat meals and 3–4 fold with high-fat meals.

Distribution: Lapatinib is highly protein-bound (>99%), mainly to albumin and alpha-1 acid glycoprotein. It is a substrate for transport proteins such as BCRP and P-glycoprotein and can inhibit these transporters as well as hepatic uptake transporter OATP1B1 at clinically relevant concentrations.

Metabolism: Lapatinib is extensively metabolized in the liver, primarily by CYP3A4 and CYP3A5 enzymes, with minor contributions from CYP2C19 and CYP2C8. The resulting metabolites contribute minimally to overall drug activity.

Metabolism : Lapatinib is extensively metabolized in the liver, primarily by CYP3A4 and CYP3A5 enzymes, with minor contributions from CYP2C19 and CYP2C8. The resulting metabolites contribute minimally to overall drug activity.

HER2-Positive Metastatic Breast Cancer: The recommended dose of Lapatinib is 1,250 mg given orally once daily on Days 1-21 continuously in combination with Capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21-day cycle. Lapatinib should be taken at least one hour before or one hour after a meal. The dose of Lapatinib should be once daily (5 tablets administered all at once); dividing the daily dose is not recommended. Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs.

Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer: The recommended dose of Lapatinib is 1,500 mg given orally once daily continuously in combination with Letrozole. When coadministered with Lapatinib, the recommended dose of Letrozole is 2.5 mg once daily. Lapatinib should be taken at least one hour before or one hour after a meal. The dose of Lapatinib should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended.

Pediatric Use: The safety and effectiveness of Lapatinib in pediatric patients have not been established.

Effects of Lapatinib on Drug-Metabolizing Enzymes and Drug Transport Systems: Lapatinib inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp, ABCB1) at clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo. Caution should be exercised and dose reduction of concomitant substrate drugs should be considered when dosing Lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4, CYP2C8, or P-gp. Lapatinib does not significantly inhibit CYP1A2, CYP2C9, CYP2C19, and CYP2D6 in vitro.

Midazolam: Following coadministration of Lapatinib and Midazolam (a CYP3A4 substrate), 24-hour systemic exposure (AUC) of orally administered Midazolam increased by 45%, while 24-hour AUC of intravenously administered Midazolam increased by 22%.

Paclitaxel: In combination with Lapatinib and Paclitaxel (CYP2C8 and P-gp substrate), 24-hour systemic exposure (AUC) of Paclitaxel increased by 23%.

Digoxin: Following coadministration of Lapatinib and Digoxin (P-gp substrate), systemic AUC of oral Digoxin increased approximately 2.8-fold. Serum Digoxin concentrations should be monitored prior to initiation of Lapatinib and adjusted accordingly.

Ketoconazole: In healthy subjects receiving Ketoconazole (a CYP3A4 inhibitor) at 200 mg twice daily for 7 days, systemic exposure (AUC) to Lapatinib increased approximately 3.6-fold and half-life increased to 1.7-fold.

Carbamazepine: In healthy subjects receiving Carbamazepine (a CYP3A4 inducer), systemic exposure (AUC) to Lapatinib decreased approximately 72%.

Drugs That Inhibit Drug Transport Systems: Lapatinib is a substrate of P-gp (ABCB1). If administered with drugs that inhibit P-gp, increased concentrations of Lapatinib are likely.

Acid-Reducing Agents: The aqueous solubility of Lapatinib is pH dependent, with higher pH resulting in lower solubility. Esomeprazole (40 mg once daily for 7 days) did not result in a clinically meaningful reduction in Lapatinib exposure.

Lapatinib is contraindicated in patients with known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components.

The most common adverse reactions during treatment with Lapatinib plus Capecitabine were diarrhea, palmar-plantar erythrodysesthesia, nausea, rash, vomiting, and fatigue. The most common adverse reactions during treatment with Lapatinib plus Letrozole were diarrhea, rash, nausea, and fatigue.

Based on findings in animal studies and its mechanism of action, Lapatinib can cause fetal harm when administered to a pregnant woman. There are no available human data to inform of the drug-associated risks. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. There are no data on the presence of Lapatinib in human milk, or its effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions in a breastfed child from Lapatinib, advise lactating women not to breastfeed during treatment with Lapatinib and for 1 week after the last dose.

Cardiac Effects: Lapatinib may reduce left ventricular ejection fraction (LVEF). Most cases occur within the first 12 weeks of treatment. Heart function should be checked before and during treatment. Use cautiously in patients with heart disease.

Hepatotoxicity: Lapatinib may cause serious liver injury, sometimes leading to death. Liver function tests should be done regularly. If severe abnormalities occur, treatment should be stopped permanently.

Diarrhea: Diarrhea is common and may be severe. It usually occurs early during treatment. Prompt treatment with anti-diarrheal medicines is necessary. Severe cases may require fluids, electrolytes, antibiotics, or stopping the drug.

Lung Problems: Lapatinib may cause interstitial lung disease or pneumonitis. If severe breathing problems occur, the drug should be discontinued.

QT Prolongation: Lapatinib may prolong the QT interval, increasing the risk of serious heart rhythm problems. Electrolyte imbalance should be corrected before starting treatment.

Severe Skin Reactions: Serious skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis may occur. Treatment should be stopped if severe skin reactions appear.

Dose Modification Guidelines:

Cardiac Events : Lapatinib should be discontinued in patients with decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0), or if LVEF falls below the institution’s lower limit of normal (LLN). Lapatinib in combination with Capecitabine may be restarted at a reduced dose (1,000 mg/day), and in combination with Letrozole at a reduced dose of 1,250 mg/day after at least 2 weeks if LVEF returns to normal and the patient is asymptomatic.

Hepatic Impairment : Patients with severe hepatic impairment (Child-Pugh Class C) should have their Lapatinib dose reduced. A reduction from 1,250 mg/day to 750 mg/day (HER2-positive metastatic breast cancer) or from 1,500 mg/day to 1,000 mg/day (hormone receptor-positive, HER2-positive breast cancer) may help adjust AUC toward normal levels. However, clinical data supporting this adjustment are lacking.

Diarrhea: Lapatinib should be interrupted in patients with Grade 3 diarrhea or Grade 1–2 diarrhea with complications (e.g., severe abdominal cramping, nausea/vomiting ≥ Grade 2, fever, sepsis, neutropenia, bleeding, or dehydration). It may be resumed at a lower dose (1,250 → 1,000 mg/day or 1,500 → 1,250 mg/day) once diarrhea improves to Grade 1 or less. Lapatinib should be permanently discontinued in Grade 4 diarrhea.

Concomitant Strong CYP3A4 Inhibitors: Concomitant use should be avoided (e.g., Ketoconazole, Itraconazole, Clarithromycin, Ritonavir, etc.). Grapefruit should also be avoided. If unavoidable, reduce Lapatinib dose to about 500 mg/day. After discontinuation of the inhibitor, allow ~1 week washout before returning to the standard dose.

Concomitant Strong CYP3A4 Inhibitors : Concomitant use should be avoided (e.g., Ketoconazole, Itraconazole, Clarithromycin, Ritonavir, etc.). Grapefruit should also be avoided. If unavoidable, reduce Lapatinib dose to about 500 mg/day. After discontinuation of the inhibitor, allow ~1 week washout before returning to the standard dose.

Other Toxicities : Discontinue or interrupt Lapatinib if ≥ Grade 2 toxicity occurs. Restart at standard dose (1,250 or 1,500 mg/day) once toxicity improves to Grade 1 or less. If toxicity recurs, restart at reduced dose (1,000 mg/day with Capecitabine or 1,250 mg/day with Letrozole), or as directed by a physician.

There is no specific antidote for Lapatinib overdose. Symptoms may include increased side effects such as fast heart rate and inflammation. Treatment is supportive.

Cytotoxic Chemotherapy

Store below 30°C in a dry place. Keep out of reach of children.